This project seeks to identify and purify from spider venoms chemical agents which can be used to prevent or limit the death of nerve cells in the brain and spinal cord following an acute injury. Recent evidence suggests that nerve cell death in such disorders as stroke and brain trauma results in part from excessive release of the neurotransmitter glutamate, which stimulates entry of calcium ions into neurons. Thus, this project seeks to isolate novel compounds which (a) specifically block glutamate release, (b) specifically antagonize postsynaptic glutamate receptors, or (c) interfere with the accumulation of calcium in nerve cells. These activities will be detected in HPLC-fractionated spider venoms by a battery of assays, including receptor binding measurements, single-cell electrophysiology, and radioisotopic flux measurements. The chemical structure of promising compounds will be determined, and candidates for further drug development will be tested for their neuroprotective effects using established in vitro and in vivo models of nerve cell death. As there are presently no effective drug therapies for the treatment of acute brain injury, the commercial potential for neuroprotective agents is substantial.